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Insulin Glucagon; IR
Fasting & postprandial hyperglycaemia
GOLONGAN ADO
1. 2. 3. 4. 5. Insulin secretagogue Insuline sensitiziser Alfa glukosidase inhibitor Aldose reductase inhibitor Dipeptidyl Peptidase Inhibitor
INSULIN SEKRETAGOGUE
SULFONIL UREA 1. Generasi pertama - tolbutamid - klorpropamid - asetoheksamid 2. Generasi kedua - gliburid - glibenklamid - glipizid - glikasid - glimepirid
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MEKANISME KERJA
Telah dikenali 3 buah reseptor sulfonil urea SUR 1 : sel pankreas dan otak SUR 2A : jantung & otot skelet SUR 3A : otot polos SU menduduki SUR yg ada dipermukaan sel terbukanya kanal Ca Insulin dilepas
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Farmakokinetik
= Absp oral mudah = t dari gol 1 paling panjang ; klorpropa mid dari gol 2 hmpr semua panjang dapat diberikan satu kali sehari = Gol. terbaru dapat mengontrol kadar gula sirkardian lebih baik mengurangi ba haya hiperinsulinemia mis.Glikasid MR
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Interaksi obat
Dapat menyebabkan hipoglikemia berat Bila diberikan bersama: = Sulfonamid, propranolol, salisilat = Klofibrat = Fenilbutazon, probenisid = Dikumarol dan anti koagulan lain = Kloramfenikol, MAO inhibitor = Alkohol
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INSULIN SENSITIZISER
I. BIGUANID Terbentuk dari 2 molekul guanidin
Penformin
Metformin
telah dilarang penggunaan nya ok bahaya terj. Asidosis asam laktat uji klinis rampung thn l995
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Mekanisme kerja
Penurunan gula darah tidak tergantung pd fungsi sel Langerhans. Bekerja dengan cara: 1. Merangsang glikolisis anaerob lbh banyak gula masuk ke otot 2. Mengurangi glukoneogenesis di hepar 3. Memperlambat absp. gula dari GI 4. Mengurangi plasma glukagon 5. Potensiasi dgn insulin 6. Menurunkan BB pend. DM obese mekanisme blm jelas
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Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity
Liver
Gluconeogenesis Glycogenolysis Glycogen synthesis
Metformin
Blood glucose
Glucose uptake in muscle and fat by increasing insulin sensitivity5
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Muscle
Adipose tissue
Liver
1. Kirpichnikov D et al. Ann Intern Med. 2002;137:2533. 2. Setter SM et al. Clin Ther. 2003;25:29913026. 3. Hundal RS et al. Diabetes. 2000;49:20632069. 4. Chu CA et al. Metabolism. 2000;49:16191626. 5. Bailey CJ et al. N Engl J Med. 1996;334:574579.
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INSULIN SENSITIZISER
2. THIAZOLIDINEDION = Masih tergol. ADO sangat baru, sebag. msh dlm taraf uji klinis = Preparat: - Ciglitazone - Englitazone - Proglitazone - Troglitazone dilarang krn hepatotoksik - Rosiglitazone
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Mekanisme kerja
= Mekanisme kerja utama diduga meningkatkan sensitivitas jaringan target thdp insulin = Potensiasi dgn insulin ---- meningkatkan up-take glukosa & oksidasi glukosa di jar. lemak dan mengurangi output glukosa dr hepar = Agonis poten dan selektif dr PPAR PPAR-RXR mengaktivasi insulin responsive gen dan regulasi transkripsi gen memperbaiki transport dan utilisasi glukosa = Menurunkan resistensi insulin = Menurunkan insulinemia = Memperbaiki hiperglikemia pd NIDDM
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Farmakokinetik
= Absp : oral tdk dipengaruhi makanan efek klinis terlih. stlh pemakaian 6 mgg = Metab.: di hepar oleh isozim CYP2C8 CYP2C9 dan CYP3A4 = Ekskresi : mel. Ginjal ,dpt diberikan pd insufisiensi ginjal baru Troglitazon dilaporkan menybkan hepatotoksik dianjurkan pemeriksaan SGOT-SGPT selama pemberian
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Incretins
Incretins
are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. GIP Glucose-dependent insulinotropic polypeptide GIP glucagon-like peptide-1 (GLP-1) Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
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DISEKRESI SEL < PADA DISTAL USUS (ILEUM & COLON) MERANGSANG PELEPASAN GLUCOSE DEPENDENT INSULINE DARI SEL MENEKAN GLUCOSE OUT PUT DARI HEPAR DENGAN MENGHAMBAT RESPONS GLUKAGON DARI SEL (GLUCOSE DEPENDENT )
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Food ingestion
Glucose
uptake by peripheral tissue2,4
GI tract
Glucose Dependent
Glucagon from alpha cells (GLP-1)
production by liver
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GIP
DISEKRESI SEL K PADA BAGIAN PROXIMAL USUS ( DUODENUM & JEJUNUM PROXIMAL )
MERANGSANG PELEPASAN GLUCOSE DEPENDENT INSULINE DARI SEL
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JADI HAMBATAN DPP-4 MENCEGAH DEGRADAI GLP-1 & GIP MENGONTROL KADAR GULA DARAH
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JANUVIA (sitagliptin) Targets 2 Physiologic Glucose-Lowering Actions With a Single Oral Agent
Food ingestion
Glucose dependent
Release of active incretins GLP-1 and GIP
GI tract
Blood glucose
Glucose production by liver
DPP-4 enzyme
Glucose dependent
Glucagon (GLP-1)
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal.
JANUVIA blocks DPP-4 to enhance the level of active incretins for 24 hours.
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The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes Metformin Reduces Hyperglycemia in a Complementary Manner
Sitagliptin improves beta-cell function and increases insulin Beta-Cell synthesis and Dysfunction release.
Hepatic Glucose Sitagliptin reduces HGO through suppression of glucagon Overproduction (HGO) from alpha cells.
*Please see corresponding speaker note for references.
Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.
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CREUTZFELOT 1979 MENEMUKAN DPP-4 = SUATU CELL SURFACE SERINE PROTEASE KADAR ADA DI GINJAL, USUS & SS. TULANG
KADAR > DI HEPAR, PANKREAS, PLASENTA, LIEN, DLL DM TIPE 2 KADAR GLP-1, INSULIN & C. PEPTIDA
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F. KINETIK = ABSP : ORAL BAIK = CSS : HR KE-3-10 = EKSRESI : GINJAL = t : 11-14 JAM
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Pancreas
Beta-cell dysfunction
Liver
Glucose level
Insulin resistance
Biguanides
Gut
Alphaglucosidase inhibitors Biguanides
TZDs
TZDs
DPP-4 inhibitors
Glucose absorption
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:14271483.
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T H A N K
Y O U
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